The Effect of DA-9701 in Opioid-induced Bowel Dysfunction of Guinea Pig

Abstract

Background/aims: Opioid induced bowel dysfunction (OIBD) is associated with decreased gastrointestinal (GI) propulsive activity due to intake of opioid analgesics. DA-9701, a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber has promising effects on GI motor function. Therefore, we aim to evaluate the prokinetic effects of DA-9701 in an OIBD model of guinea pig.

Methods: The ileal and distal colon muscle contraction in presence of different doses of DA-9701, morphine, and combination (morphine + DA-9701) was measured by tissue bath study. The prokinetic effect of DA-9701 was assessed by charcoal transit and fecal pellet output assay in an OIBD model of guinea pig.

Results: DA-9701 significantly increased the amplitude and area under the curve of ileal muscle contraction, while there was insignificant effect on the distal colon compared to the control. The maximal amplitude of ileal muscle contraction was acquired at a concentration of 10 μg/mL of DA-9701. In contrast, morphine significantly decreased the amplitude of ileal and distal colon muscle contraction compared to the control. Morphine delayed both upper (P < 0.01) and lower (P < 0.05) GI transit, and delayed GI transit was restored by the administration of DA-9701. Morphine induced reduction of contractility was significantly ameliorated by addition of DA-9701 in both ileal and distal colon muscles.

Conclusions: DA-9701 significantly increased the amplitude of contraction of the ileal muscle, however the distal colon muscle contraction was insignificant. Additionally, it restored delayed upper and lower GI transit in an OIBD model of guinea pig, and it might prove to be a useful candidate drug in a clinical trial for OIBD.

Keywords: DA-9701; Gastrointestinal transit; Ileum; Morphine; Opioid.

Figure 1

Effect of DA-9701 on contraction of the ileal muscle. DA-9701 increased maximal amplitude and area under the curve in a dose dependent manner (1–10 μg/mL). (A) The percent change of amplitude from control (*P = 0.010). (B) The percent change of under the curve (AUC) from control (*P = 0.010) Values are represented in mean ± SEM.

Figure 2

Effect of DA-9701 on contraction of the distal colon muscle. DA-9701 increased amplitude and under the curve (AUC) compared to that of control. Values are represented in mean ± SEM.

Figure 3

Effects of morphine on contraction of the ileal muscle. Morphine decreased maximal amplitude and area under the curve (AUC). (A) Percent change of amplitude from control (*P = 0.010). (B) Percent change of AUC from control. Values are represented in mean ± SEM.

Figure 4

Effects of Morphine on contraction of the distal colon muscle. Morphine decreased maximal amplitude and area under the curve (AUC). (A) Percent change of amplitude from control (*P = 0.010). (B) Percent change of AUC from control (*P = 0.010) Values are represented in mean ± SEM.

Figure 5

Effect of different doses of morphine on upper gastrointestinal transit in the guinea pig. Values are mean ± SEM. *P < 0.05 and **P < 0.01 in comparison to control.

Figure 6

Effect of different doses of morphine on lower gastrointestinal transit in guinea pig. (A) Effect of different concentrations of morphine on cumulative fecal pellet output (FPO). (B) Effect of different concentrations of morphine on cumulative FPO weight (g). Values are mean ± SEM. *P < 0.05 in comparison to control.

Figure 7

Effect of DA-9701 on morphine treated ileal muscle. DA-9701 increased maximal amplitude and under the curve (AUC) at concentrations of 20 μg/mL. (A) Percent change of amplitude from morphine only (*P = 0.010). (B) Percent change of AUC from morphine only (*P = 0.010). Values are represented in mean ± SEM.

Figure 8

Effect of DA-9701 on morphine treated distal colon muscle. DA-9701 increased maximal amplitude and under the curve (AUC) at concentrations of 20 μg mL⁻¹. (A) Percent change of amplitude from morphine only (*P = 0.01). (B) Percent change of AUC from morphine only (*P = 0.01). Values are represented in mean ± SEM.

Figure 9

The effect of DA-9701 on upper gastrointestinal transit in opioid induced bowel dysfunction guinea pig model. Values are mean ± SEM. *P < 0.05 and **P < 0.01 in comparison to morphine only.

Figure 10

Effect of DA-9701 on (A) cumulative fecal pellet number and (B) cumulative fecal weight mean ± SEM (n = 6/group); *P < 0.05 and **P < 0.01 in comparison to morphine only.